Nanomedicine-protein interactions: Understanding protein corona composition effects on nanomedicine cellular uptake

纳米药物-蛋白质相互作用：了解蛋白质冠成分对纳米药物细胞摄取的影响

• 批准号: 2275000
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2275000
• 关键词: Nanomedicine; protein; interactions; Understanding; corona

From bench to clinic, a new drug candidate will face multiple roadblocks and challenges in its development. In oncology drug development, a balance has to be met between achieving tumour bioavailability and potential off-target organ toxicity- Nanomedicines have emerged as a promising solution to overcoming such challenges. When administered intravenously, a nanomedicine will be exposed to various biomolecules in blood. Some of these molecules will adsorb onto the nanomedicine surface, forming a 'corona', altering its chemical identity and biological fate. Hydrophobic nanomedicines have a shorter circulation half-life owing to a higher degree of opsonisation and subsequent clearance following recognition by the mononuclear phagocytic system. In a bid to improve circulation half-lives through reduced immune recognition clearance, stealthing with hydrophilic molecules such as PEG has been implemented as a standard approach in nanomedicine research.This studentship will investigate how nanoparticle physicochemical characteristics impact protein corona formation on nanoparticle surfaces, and the subsequent impact of protein corona formation on nanomedicine physicochemical characteristics and cellular interactions. Orthogonal particle metrology technologies will be applied to the characterization of nanomedicine physicochemical characteristics prior to and following protein corona treatment in plasma and cellular lysate. A limited number of studies to date have evaluated the impact of protein corona formation on nanomedicine physicochemical characteristics and subsequent biological fate. PLGA nanoparticles will be investigated as a model due to their extensive investigation as nanocarriers, established safety profile, maturity in the clinic, and significant lack of published reports on NP corona characterization. Findings from this work, in combination with parallel proteomics analysis offer the scope for developing predictive models of nanomedicine biological fate. This studentship will be the first of a series considering both dynamic and endpoint characterization of nanoparticle protein corona evolution over various timescales as a function of nanoparticle physicochemical attributes. Understanding protein corona composition has been recognized as a critical factor in deconvoluting the interplay between particle manufacture processes, critical quality attributes, and subsequent in vivo performance. Ultimately, predictive models of nanomedicine biological fate will create a step-change in the design and construction of novel nanomedicines with tunable protein corona profiles that can be exploited to improve drug biodistribution and therapeutic efficacy.

从实验室到临床，新药候选人在开发过程中将面临多重障碍和挑战。在肿瘤药物开发中，必须在实现肿瘤生物利用度和潜在的脱靶器官毒性之间取得平衡-纳米医学已成为克服这些挑战的有希望的解决方案。当静脉注射时，纳米药物将暴露于血液中的各种生物分子。其中一些分子会吸附在纳米药物表面，形成“冠状”，改变其化学身份和生物命运。由于更高程度的调理作用和随后被单核吞噬系统识别后的清除，疏水性纳米药物具有更短的循环半衰期。为了通过减少免疫识别清除来改善循环半衰期，使用亲水性分子（如PEG）进行隐形已经成为纳米医学研究的标准方法。本研究将研究纳米颗粒的理化特性如何影响纳米颗粒表面的蛋白质冠形成，以及蛋白质冠形成对纳米医学理化特性和细胞相互作用的后续影响。正交粒子计量技术将被应用到纳米药物的物理化学特性的表征之前和之后的蛋白质电晕处理在血浆和细胞裂解物。到目前为止，有限数量的研究已经评估了蛋白质冠形成对纳米医学理化特性和随后的生物命运的影响。PLGA纳米颗粒将作为模型进行研究，因为其作为纳米载体进行了广泛的研究，建立了安全性特征，临床成熟，并且显著缺乏关于NP冠状表征的已发表报告。这项工作的发现，结合平行蛋白质组学分析，为开发纳米医学生物命运的预测模型提供了范围。该研究将是一系列研究中的第一个，这些研究考虑了纳米颗粒蛋白质冠在不同时间尺度上的动态和终点表征，作为纳米颗粒物理化学属性的函数。了解蛋白质冠组成已被认为是消除颗粒制造工艺、关键质量属性和后续体内性能之间相互作用的关键因素。最终，纳米药物生物命运的预测模型将在设计和构建具有可调蛋白质冠状分布的新型纳米药物方面产生重大变化，这些蛋白质冠状分布可用于改善药物的生物分布和治疗效果。